Search

Background: Immune-mediated necrotizing myopathy (IMNM), a subgroup of idiopathic inflammatory myopathies (IIMs), is characterized by severe proximal muscle weakness and prominent necrotic fibers but no infiltration of inflammatory cells. IMNM pathogenesis is unclear. This study investigated key biomarkers and potential pathways for IMNM using high-throughput sequencing and bioinformatics technology. Methods: RNA sequencing was conducted in 18 IMNM patients and 10 controls. A combination of weighted gene coexpression network analysis (WGCNA) and differentially expressed gene (DEG) analysis was conducted to identify IMNM-related DEGs. Feature genes were screened out by employing the proteinprotein interaction (PPI) network, support vector machine-recursive feature elimination (SVM-RFE), and least absolute shrinkage selection operator (LASSO). Quantitative real-time polymerase chain reaction (qRTPCR) was performed to verify their differential expression, and the receiver operating characteristic curve (ROC) was used to evaluate their diagnostic efficiency. Functional enrichment analysis was applied to reveal the hidden functions of feature genes. Furthermore, 28 immune cell abundance patterns in IMNM samples were measured. Results: We identified 193 IMNM-related DEGs that were aberrantly upregulated in the IMNM population and were closely associated with immune-inflammatory responses, regulation of skeletal and cardiac muscle contraction, and lipoprotein metabolism. With the help of the PPI network and the LASSO and SVM-RFE algorithms, three feature genes, LTK, MYBPH, and MYL4, were identified and further confirmed by qRTPCR. ROC curves among IMNM, dermatomyositis (DM), inclusion body myositis (IBM), and polymyositis (PM) samples validated the LTK and MYL4 genes as IMNM-specific feature markers. In addition, all three genes had a notable association with the autophagylysosome pathway and immune-inflammatory responses. Ultimately, IMNM displayed a marked immune-cell infiltrative microenvironment. The most significant correlation was found between CD4 T cells, CD8 T cells, macrophages, natural killer (NK) cells, and dendritic cells (DCs). Conclusions: LTK, MYBPH, and MYL4 were identified as potential key molecules for IMNM and are believed to play a role in the autophagylysosome pathway and muscle inflammation.

Abstract Background Lung cancer (LC) is one of the most common cancers and a leading cause of cancer‐related deaths worldwide. In many pathological conditions, particularly in the tumor microenvironment, cells and tissues frequently exist in a hypoxic state. Here, we evaluated Itchy E3 ubiquitin protein ligase (ITCH) expression in LC cells following hypoxia treatment. Methods LC cell lines were treated with hypoxic condition. Cell migration, invasion, inflammation, reactive oxygen species (ROS) production, and apoptosis of LC cells were determined by wound healing assay, Transwell invasive assay, ELISA, DCFH‐DA staining, and flow cytometry, respectively. qPCR and WB were used to determine the expression of ITCH and TXNIP. Co‐IP was performed to assess the interaction between ITCH and TXNIP. Results ITCH expression was downregulated in LC cells under hypoxic conditions. Next, LC cells were subjected to hypoxic conditions and changes in cell viability and metastasis were determined. Hypoxic conditions resulted in increased migration and invasion abilities of LC cells. Intracellular reactive oxygen species (ROS) production, inflammation, and apoptosis were also promoted by hypoxia. We found that ITCH overexpression led to the proteasomal degradation of thioredoxin‐interacting protein (TXNIP), whereas the expression of the ITCH C830A mutant did not affect TXNIP levels in LC cells. The gain‐of‐function experiment demonstrated that migration, invasion, ROS generation, inflammation, and apoptosis of hypoxia‐conditioned LC cells were ameliorated by ITCH overexpression, whereas the ITCH C830A mutant did not cause any changes in these phenotypes. Furthermore, the contribution of TXNIP knockdown and ITCH overexpression to the hypoxia‐induced features in LC cells with ITCH C830A was found to be similar. Conclusion Our results suggest a novel mechanism underlying the changes in ITCH‐mediated malignant phenotypes of hypoxia‐conditioned LC cells via TXNIP.

BackgroundInclusion body myositis (IBM) is a slowly progressive inflammatory myopathy that typically affects the quadriceps and finger flexors. Sjögren’s syndrome (SS), an autoimmune disorder characterized by lymphocytic infiltration of exocrine glands has been reported to share common genetic and autoimmune pathways with IBM. However, the exact mechanism underlying their commonality remains unclear. In this study, we investigated the common pathological mechanisms involved in both SS and IBM using a bioinformatic approach.MethodsIBM and SS gene expression profiles were obtained from the Gene Expression Omnibus (GEO). SS and IBM coexpression modules were identified using weighted gene coexpression network analysis (WGCNA), and differentially expressed gene (DEG) analysis was applied to identify their shared DEGs. The hidden biological pathways were revealed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Furthermore, protein−protein interaction (PPI) networks, cluster analyses, and hub shared gene identification were conducted. The expression of hub genes was validated by reverse transcription quantitative polymerase chain reaction (RT−qPCR). We then analyzed immune cell abundance patterns in SS and IBM using single-sample gene set enrichment analysis (ssGSEA) and investigated their association with hub genes. Finally, NetworkAnalyst was used to construct a common transcription factor (TF)-gene network.ResultsUsing WGCNA, we found that 172 intersecting genes were closely related to viral infection and antigen processing/presentation. Based on DEG analysis, 29 shared genes were found to be upregulated and enriched in similar biological pathways. By intersecting the top 20 potential hub genes from the WGCNA and DEG sets, three shared hub genes (PSMB9, CD74, and HLA-F) were derived and validated to be active transcripts, which all exhibited diagnostic values for SS and IBM. Furthermore, ssGSEA showed similar infiltration profiles in IBM and SS, and the hub genes were positively correlated with the abundance of immune cells. Ultimately, two TFs (HDGF and WRNIP1) were identified as possible key TFs.ConclusionOur study identified that IBM shares common immunologic and transcriptional pathways with SS, such as viral infection and antigen processing/presentation. Furthermore, both IBM and SS have almost identical immune infiltration microenvironments, indicating similar immune responses may contribute to their association.

BackgroundDysferlinopathy refers to a group of muscle diseases with progressive muscle weakness and atrophy caused by pathogenic mutations of the DYSF gene. The pathogenesis remains unknown, and currently no specific treatment is available to alter the disease progression. This research aims to investigate important biomarkers and their latent biological pathways participating in dysferlinopathy and reveal the association with immune cell infiltration.MethodsGSE3307 and GSE109178 were obtained from the Gene Expression Omnibus (GEO) database. Based on weighted gene co-expression network analysis (WGCNA) and differential expression analysis, coupled with least absolute shrinkage and selection operator (LASSO), the key genes for dysferlinopathy were identified. Functional enrichment analysis Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to disclose the hidden biological pathways. Following that, the key genes were approved for diagnostic accuracy of dysferlinopathy based on another dataset GSE109178, and quantitative real-time polymerase chain reaction (qRT-PCR) were executed to confirm their expression. Furthermore, the 28 immune cell abundance patterns in dysferlinopathy were determined with single-sample GSEA (ssGSEA).Results1,579 differentially expressed genes (DEGs) were screened out. Based on WGCNA, three co-expression modules were obtained, with the MEskyblue module most strongly correlated with dysferlinopathy. 44 intersecting genes were recognized from the DEGs and the MEskyblue module. The six key genes MVP, GRN, ERP29, RNF128, NFYB and KPNA3 were discovered through LASSO analysis and experimentally verified later. In a receiver operating characteristic analysis (ROC) curve, the six hub genes were shown to be highly valuable for diagnostic purposes. Furthermore, functional enrichment analysis highlighted that these genes were enriched mainly along the ubiquitin-proteasome pathway (UPP). Ultimately, ssGSEA showed a significant immune-cell infiltrative microenvironment in dysferlinopathy patients, especially T cell, macrophage, and activated dendritic cell (DC).ConclusionSix key genes are identified in dysferlinopathy with a bioinformatic approach used for the first time. The key genes are believed to be involved in protein degradation pathways and the activation of muscular inflammation. And several immune cells, such as T cell, macrophage and DC, are considered to be implicated in the progression of dysferlinopathy.

BackgroundHypertrophic cardiomyopathy (HCM) is the prevalent inherited cardiomyopathy and a major contributor to sudden death and heart failure in young adults. Although depression has been associated with poor prognosis in patients with cardiovascular disease, the relationship between anxiety and HCM clinical outcomes has not been addressed. We aimed to determine the prevalence of anxiety symptoms in patients with HCM and the association between anxiety and adverse prognosis in this population.MethodsA total of 793 patients with HCM were prospectively enrolled and followed up for a mean of 4.1 years from March 2014 to January 2018. The primary endpoint was sudden cardiac death (SCD) events, and the secondary endpoint was HCM-related heart failure events. Anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) during outpatient visits or hospital stays.ResultsElevated scores on the HADS anxiety subscale (HADS-A ≥ 8) were defined as clinically significant anxiety. SCD and HCM-related heart failure events occurred in 76 and 149 patients, respectively, during the follow-up period. Kaplan–Meier survival curves demonstrated the significant association of anxiety with SCD events (log-rank P = 0.012) and HCM-related heart failure events (log-rank P = 0.001). Multivariable Cox regression analysis showed anxiety as a predictor of SCD events and HCM-related heart failure events (adjusted hazard ratio [HR] = 1.42, 95% confidence interval [CI] = 1.12–2.04, P = 0.03; adjusted HR = 2.9,2 95% CI = 1.73–4.03, P < 0.001), independent of conventional risk factors and depression. Besides, patients with comorbid anxiety and depression showed a fourfold higher risk of heart failure events and 3.5-fold higher risk of SCD versus those with neither (adjusted HR = 4.08, 95% CI = 2.76–5.91, P < 0.001; adjusted HR = 3.52, 95% CI = 2.24–4.67, P < 0.001, respectively).ConclusionsAnxiety was prevalent among Chinese patients with HCM, and it was independently associated with a higher risk of SCD and HCM-related heart failure events, particularly when comorbid with depression. Psychological assessment and intervention should be considered to alleviate anxiety symptoms in this population.Clinical Trial Registrationhttp://www.chictr.org.cn, identifier: ChiCTR2000040759.

BackgroundA pocket hematoma is a well-recognized complication that occurs after pacemaker or defibrillator implantation. It is associated with increased pocket infection and hospital stay. Patients suffering from atrial fibrillation and undergoing cardiovascular electronic implantable device (CIED) surgery are widely prescribed and treated with direct oral anticoagulants (DOACs). In this study, the use of a novel compression device was evaluated to examine its ability to decrease the incidence of pocket hematomas following device implantation with uninterrupted DOACs.MethodsA total of 204 participants who received DOACs and underwent CIED implantation were randomized into an experimental group (novel compression device) and a control group (elastic adhesive tape with a sandbag). The primary outcome was pocket hematoma, and the secondary outcomes were skin erosions and patient comfort score. Grade 3 hematoma was defined as a hematoma that required anticoagulation therapy interruption, re-operation, or prolonged hospital stay.ResultsThe baseline characteristics of both groups had no significant differences. The incidence of grades 1 and 2 hematomas was significantly lower in the compression device group than in the conventional pressure dressing group (7.8 vs. 23.5 and 2.0 vs. 5.9%, respectively; P < 0.01). Grade 3 hematoma occurred in 2 of 102 patients in the experimental group and 7 of 102 patients in the control group (2.0 vs. 6.9%; P = 0.03). The incidence rates of skin erosion were significantly lower, and the patient comfort score was much higher in the compression device group than in the control group (P < 0.01). Multivariable logistic regression analysis showed that the use of novel compression device was a significant protective factor for pocket hematoma (OR = 0.42; 95% CI, 0.29–0.69, P = 0.01).ConclusionsThe incidence of pocket hematomas and skin erosions significantly decreases when the proposed compression device is used for patients undergoing device implantation with uninterrupted DOACs. Thus, the length of hospital stay and re-operation rate can be reduced, and patient comfort can be improved.Clinical Trial Registrationhttp://www.chictr.org.cn, identifier: ChiCTR2100049430.

BackgroundMyocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous entity with varying underlying etiologies and occurs in ~5–10% of patients with acute myocardial infarction. Sleep disorders and short sleep duration are common phenomena experienced by patients with coronary heart disease and are associated with poor clinical outcomes. However, the association between sleep quality, sleep duration, and the MINOCA prognosis is less clear.MethodsWe performed a prospective observational study of 607 patients with MINOCA between February 2016 and June 2018. The mean follow-up period was 3.9 years. Sleep quality and sleep duration were measured by the Chinese version of the Pittsburgh Sleep Quality Index. The primary endpoint was all-cause mortality, and the secondary endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, stroke and heart failure hospitalization.ResultsDuring the follow-up period, all-cause death occurred in 69 participants and 105 participants developed MACE. The Kaplan–Meier survival analysis demonstrated a significant association between poor sleep quality and all-cause mortality (log-rank P = 0.005) and MACE (log-rank P = 0.004). Multivariable Cox regression model indicated that poor sleep quality was an independent predictor of all-cause mortality as well as MACE [adjusted hazard ratio (HR) = 1.649; 95% confidence interval (CI), 1.124–2.790; P < 0.001; and adjusted HR = 1.432; 95% CI, 1.043–2.004; P = 0.003, respectively]. For sleep duration, short sleep duration (8 h/d). A poorer sleep profile (including poor sleep quality and short sleep duration) was associated with a 149.4% increased risk of death (HR = 2.494; 95% CI, 1.754–4.562; P < 0.001) and a 96.7% increased risk of MACE (HR = 1.967; 95% CI, 1.442–3.639; P < 0.001) than those with neither.ConclusionSleep disorders were common among Chinese patients with MINOCA. Poor sleep quality and short sleep duration were independently associated with an increased risk of all-cause mortality and MACE in the MINOCA population. Meanwhile, a poor sleep profile has an additive effect with regard to cardiovascular risks; in these populations, efforts should be made to improve both sleep quality and sleep duration for secondary cardiovascular prevention.Clinical Trial Registrationhttp://www.chictr.org.cn, identifier: ChiCTR2000040701.

Background and Aims: Weight-loss diets reduce body weight and improve blood pressure control in hypertensive patients. Intermittent energy restriction (IER) is an alternative to continuous energy restriction (CER) for weight reduction. We aimed to compare the effects of IER with those of CER on blood pressure control and weight loss in overweight and obese patients with hypertension during a 6-month period.Methods: Two hundred and five overweight or obese participants (BMI 28.7 kg/m2) with hypertension were randomized to IER (5:2 diet, a very-low-calorie diet for 2 days per week, 500 kcal/day for women and 600 kcal/day for men, along with 5 days of a habitual diet) compared to a moderate CER diet (1,000 kcal/day for women and 1,200 kcal/day for men) for 6 months. The primary outcomes of this study were changes in blood pressure and weight, and the secondary outcomes were changes in body composition, glycosylated hemoglobin A1c (HbA1c), and blood lipids.Results: Of the 205 randomized participants (118 women and 87 men; mean [SD] age, 50.2 [8.9] years; mean [SD] body mass index, 28.7 [2.6]; mean [SD] systolic blood pressure, 143 [10] mmHg; and mean [SD] diastolic blood pressure, 91 [9] mmHg), 173 completed the study. The intention-to-treat analysis demonstrated that IER and CER are equally effective for weight loss and blood pressure control: the mean (SEM) weight change with IER was −7.0 [0.6] kg vs. −6.8 [0.6] kg with CER, the mean (SEM) systolic blood pressure with IER was −7 [0.7] mmHg vs. −7 [0.6] mmHg with CER, and the mean (SEM) diastolic blood pressure with IER was −6 [0.5] mmHg vs. −5 [0.5] mmHg with CER, (diet by time P = 0.62, 0.39, and 0.41, respectively). There were favorable improvements in body composition, HbA1c, and blood lipid levels, with no differences between groups. Effects did not differ according to completer analysis. No severe hypoglycemia occurred in either group during the trial.Conclusions: Intermittent energy restriction is an effective alternative diet strategy for weight loss and blood pressure control and is comparable to CER in overweight and obese patients with hypertension.Clinical Trial Registration:http://www.chictr.org.cn, identifier: ChiCTR2000040468.